Aminoalkyl-phenyl lactones



Patented Dec. 13, 1949 AMINOALKYL-PHENYL LAC'I'ONES Arthur W. Weston, Waukcgan, 111., assignor to Abbott Laboratories, Chicago, Ill., a corporation of Illinois No Drawing. Application August 17, 1945,

Serial No. 511,201

6 Claims. (Cl. 260344) This invention relates generally to therapeutic substances and more specifically to lactones (organic compounds) which are useful as antispasmodics and the intermediates for preparing those compounds.

Example I a-(2-diethylaminoethyl)-a-phenylvalerolactone CHiGH:N(Ci i)i Ulla-CH 22 g. of a- (2-diethylaminoethyl) -benzyl cyanide is converted to its sodium salt by treatment with an ether suspension of 3.0 g. of sodamide. After the addition of 21.5 g. of 3-phenoxypropyl bromide, the mixture is refluxed and stirred several hours. The ether layer is washed with water and then extracted with dilute acid. Addition of aqueous alkali to these acidic extracts regenerates the free base which is taken up by ether. Removal of the ether leaves an oil from which any unreacted starting material is removed by heating to 200 C. at 3 mm. pressure. The residual Example 11 a-(2-diethylaminoethyl)-aphenylbutyrolactone CHICH2N(C2HI)I o CHrCi g. of a-(2-hydroxyethyl) -benzyl cyanide is refluxed and stirred four hours with 200 cc. of ether containing a suspension of sodamide prepared from 7.8 g. of sodium metal. The 2-diethylaminoethyl chloride. obtained from 34 g. of the 2 corresponding hydrochloride, is then added and the mixture stirred and refluxed several hours. The basic fraction obtained as described in the previous example is subjected to distillation. The e-(Z-hydrOXyethyD-a (2 diethylaminoethyD- benzyl cyanide has boiling point 187-190 C. at

3-4 mm., and 11 1.5127.

After refluxingl-Ll s. of this nitrile with cc. of 48 hydrobromic acid for several hours, the

solution is evaporated to dryness on the steam bath. Excess thionyl chloride is then added. The mixture is heated to remove the excess of the reagent, then cooled and stirred with ice and ether. The aqueous extracts are made alkaline and the liberated base dissolved in ether. The ether extracts are concentrated and the residue distilled. The product boils at 161-163 C. at 2-3 mm. and has 11;", 1.5203.

All of the lactones which are not quaternary ammonium salts are usually more soluble in water as salts than as the free bases and are therefore, administered as water soluble salts when rapid etlect is desired. The salts may be formed by allowing equivalent amounts of the lactone and the desired acidic material to react in the presence of a suitable organic solvent. Any acid which produces a water-soluble salt and does not appreciably enhance the toxicity is suitable for use. Such acids as sulphuric, phosphoric, hydrochloric, levulinic, mucic, acetic and tartaric acid are among those which are satisfactory. The salts produced by combination of these lactones with certain other non-toxic acids, such as tannic acid, are very sparingly soluble in water. These sparingly soluble compounds, as well as the free bases, may be administered when the pharmacological effect desired should be slow in onset and relatively long in duration. Where any lactone which does not contain a quarternary ammonium group is mentioned in the following claims, it is intended to include both the free base and the salts.

Example III Quaternary ammonium salts of the lactones already mentioned may be produced by mixing the lactones with a slight excess of an alkyl halide, a dialkyl ester of sulphuric acid, or alkyl esters of sulphonic acids. The two substances 3 may be mixed, with or without the addition of an appropriate organic solvent.

c-(Z-diethylaminoethyl)-a-phenylbutyrolaetone Two grams of a-(2-dlethylaminoethyll -o'.- phenylbutyrolactone and 1.4 grams of methyl iodide were mixed. The reaction proceeds spontaneously with generation of considerable heat,

desirable. standing.

Without further elaboration, the foregoing will so fully explain my invention, that others may readily adapt the same for use under various conditions of service. For instance, this work has established that the desired therapeutic ac-- tivity is primarily associated with a lactone ring having a side chain containingan amino group, and those skilled in this art will be aware that 'thephenyl group of the specific examples given may be replaceable by a wide variety of other groups, either aromatic or aliphatic. The length of the alkyl groups may also be varied. and branched chains of carbon atoms used instead of straight chains. In the above formulas the CH: groups in the lactone ring may be represented as ('cHzlm, where a: h asmall whole number from 2 to 4 inclusive.

I claim:

1. Aminoaikyl-phenyl lactones represented by the formula l Ph- C=O where Ph represents a phenyl group R1 represents a lower alkyl group, R: and R: are selected 'irom the group consisting of hydrogen and lower 4 to a carboxyl group, and condensing said hygggxyl and carboxyl groups to form the lactone\ 3. The process of preparing an aminoalkylphenyl lactone compound of claim 1, which comprises reacting an a-(hydroxyalkyll-benzyl cyanide with an alkali metal to form th corresponding a-alkali metal salt, reacting the resulting alkali metal salt with an aminoalkyl halide, hydrolyzing the resulting a-(hydroxyalkyl) -a-(aminoalkyl) -benzyl cyanide to convert the cyanide group to a-carboxyl group, .and condensing said carboxyl group with the hydroxyl group of said drox alk l mu t f such that external cooling of the container is y y g p 0 mm the lactone ring The crystalline product separates on 4. The compound a-(Z-diethyIamino ethyl) -1- phenylvalerolactone represented by the formula:

- CHlCH2N(C1HI)I o (CH:)3/

'5. The compound s-Q-diethyIaminoethyI)-mphenylbutyrolactone represented by the formula CH:CH1N(C25)1 H:):/ 6.,Compounds of the formula:

m-N B.

m),-0 where'Ar is an aryl group, R1 is an aliphatic group, R2, R3 and-R4 are selected from the class consisting of hydrogenand'alkyl groups, Y is a halogen atom and a: is a small whole number.

' ARTHUR W. WESTON.

REFERENCES CITED The iollowingreferences are of record in the file of this patent: I

UNITED STATES PATENTS Ar-C Germany Aug. 4, 193 8: 

